This application, in response to RFA: MH-03-008 (National Cooperative Drug Discovery Groups for the Treatment of Mood Disorders or Nicotine Addiction, NC 336-MD/NA), proposes the creation of"The Emory-GSK-NIMH Collaborative Mood Disorders Initiative." This unique opportunity to accererate antidepressant drug development brings together expertise of three complementary research groups: the Emory University School of Medicine Department of Psychiatry and Behavioral Sciences, the Mood and Anxiety Disorders Program at NIMH and the Center for Excellence in Drug Discovery (CEDD) in Psychiatry of GlaxoSmithKline (GSK), one of the largest multinational pharmaceutical companies. The two major goals of the current application are the development of innovative new models for basic and clinical research in mood disorders and the intensive scrutiny of 5 novel GSK antidepressant candidates in preclinical and clinical paradigms. In addition to an Administrative and Animal/Assay Core, 7 research projects are proposed. Of these, two are based in the intramural NIMH program; Neurogenesis, Synaptic Plasticity and Signal Transduction (Husseni Manji, M.D., PI) and Clinical Models to Assess Novel Antidepressants (Dennis S. Charney, M.D., PI). The remainder are based at Emory University led by established investigators including Jay M. Weiss, Ph.D. (Animal Models of Depression), Michael Davis, Ph.D. (Animal Models of Fear and Anxiety), Clinton D. Kilts, Ph.D. and Mark Goodman, Ph.D., (Functional Brain Imaging, with a focus on new PET ligand development), Michael J. Owens, Ph.D. and Charles B. Nemeroff, M.D., Ph.D. (Ex Vivo Assessment of Neurotransmitter Receptor and Transporter Occupancy of Antidepressants), and Andrew H. Miller, MD (Cytokine Induced Depression: A Rhesus Monkey Model). In conjunction with GSK, 5 novel GSK antidepressant candidates and others that become available via GSK Drug Discovery within the lifetime of the grant will be intensively scrutinized to synergize with the in-house GSK effort. This proposal encompasses virtually all of the major goals outlined in the RFA, namely, development of new neurochemical tools including novel PET ligands, exploration of new models of drug development and facilitation of a partnership between academia, NIMH and industry.